FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION (See Section 10)
A NOVEL CRYSTALLINE FORM Am OF CELECOXIB AND PROCESS FOR
PREPARATION THEREOF
M/S AMOLI ORGANICS PVT. LTD, 407 DALAMAL HOUSE, J.B.ROAD, NARIMAN POINT, MUMBAI-400021, INDIA, an Indian company incorporated under
the companies Act, 1956
The following specification particularly describes and ascertains the nature of this invention, and the manner in which it is to be performed.

TITLE: A NOVEL CRYSTALLINE FORM Am OF CELECOXIB AND PROCESS
FOR PREPARATION THEREOF
FIELD OF INVENTION
The present invention relates to a novel crystalline form Am of Celecoxib, to processes for preparing it and to pharmaceutical composition containing it.
BACKGROUND OF THE INVENTION
The present invention relates to novel crystalline form Am of Celecoxib and process for preparation thereof, which is known by the chemical name 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide useful as a pharmaceutical agent for the treatment of Cyclooxygetiase mediated conditions and disorders. The novel crystalline form of the present invention is useful as inhibitors of the enzyme Cyclooxygenase II (COX II) and thus it is useful as anti-inflammatory and analgesic agent.
Celecoxib is currently marketed under the name CELEBREX by Pharmacia Corporation, the empirical formula of the compound is C17H14F3N3O2S, molecular weight is 381.37 and molecular structure can be represented by foi-mula (I)

Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) mainly used in treatment of arthritis, pain, menstrual cramps, and colonic polyps. Celecoxib blocks the enzyme (Cyclooxygenase 2) which makes prostaglandins, resulting in lowering the concentrations

of prostaglandins. As a consequence, reduction in inflammation and its accompanying pain, fever, swelling and tenderness.
The manufacture of Celecoxib has been described in various patents and to cite a few references, G. D. Searl & Co. has disclosed method for preparation of Celecoxib in US 5,466,823

Which comprises, reacting 4-methyl acetophenone (II) with I-ethyltrifluoroacetate in the presence of methyl t-butyl ether and sodium methoxide followed by recrystallization from isooctane to produce l-(4-methylphenyl)-4,4,4-trifluorobutane-l,3-dione (IV), which is further condensed with 4-hydrazynophenyl sulfonamide hydrochloride (V) in the presence of ethanol to produce crude Celecoxib, which is recrystallised from ethyl acetate and isooctane to give Celecoxib, few more prior art available in Celecoxib are US 5,134,142 Matsuo et al, US 5,563,165, US 6,150,534, US 5,892,053, US 2007/0004924, US 2008/0234491, EP 1,528,058, EP 1,167,355, EP 2,246,332, WO 01/42221, WO 03/090730, WO 05/014546, WO 06/051340, WO 08/145733, and WO 2010/095024. And disclosed in literature: Org. Process Res. Dev., 2009,13(1), pp 98-101. Reddy et, al.

Celecoxib crystals may give formulation difficulties as a result of unique physical and chemical characteristics or mechanical properties such as electrostatic and cohesive properties, low bulk density, low compressibility and poor flow properties. Due at least in part to these properties, Celecoxib crystals tend to segregate and agglomerate together during mixing, resulting in a non-uniformly blended composition containing undesirably large, insoluble aggregates of Celecoxib. For these and other reasons, therefore, it is difficult to prepare an orally deliverable, rapid-onset composition containing Celecoxib that has the desired blend uniformity.
International application no. WO 00/32189 discloses specific Celecoxib composition. In this application a number of problem concerning the formulation of this agent, inter alia, its cohesiveness, low bulk density, low compressibility, and poor solubility are described. According to this document, these disadvantages are caused by the crystal structure of Celecoxib. Unformulated Celecoxib, which has a crystal morphology that tends to form long cohesive needles, typically fuses with a monolith mass upon compression in a tablet die, which leads to problem in blending the agent uniformly. Further, low bulk density causes problems in processing the small quantities required in the formulation of pharmaceutical composition.
U.S. Patent No. 7,476,744 discloses Form I, Form II, and Form III of Celecoxib. Therapeutic and general properties related advantages may yet be realized by other undiscovered forms of Celecoxib.
A need for new forms of Celecoxib. in particular form suitable for preparing rapid-onset compositions, exists. Rapid-onset drug-delivery systems can provide significant benefits over conventional dosage forms. Generally, rapid-onset preparations provide a short period to therapeutic or prophylactic response compared to conventional immediate-release or sustained-release dosage forms. For example, in treatment of acute pain, a rapid-onset dosage form of Celecoxib would be useful to provide fast pain relief.
We have now surprisingly and unexpectedly found that Celecoxib can be prepared in its novel crystalline form. Thus, the present invention provides Celecoxib in new crystalline form Am and process for preparation thereof,

SUMMARY OF THE INVENTION
The present invention is directed to novel crystalline form of Celecoxib designated as form Am. The present invention further provides a process for preparing new crystalline form of Celecoxib. The object of the present invention, therefore, is to avoid the problems produced by the known, needle-like crystalline form. The solution of this object is provided by the new crystalline form of Celecoxib as disclosed herein, which we have called "form Am" of Celecoxib, and by the corresponding production method, as also described herein. in one aspect there is provided a process for preparation of celecoxib of the formula (1):

the process include reacting a compound of formula (2) with a compound of the formula (3) in water.

In another aspect, there is provided a process for purification of Celecoxib and crystallization comprises;

(i) Providing a solution of Celecoxib in a mixture of aliphatic ketone and aromatic
hydrocarbon solvent;
(ii) Causing crystallization in said solution to obtain a solid precipitate;
(iii) Isolating the solid precipitate as substantially purified Celecoxib in its novel
crystalline form.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is an X-ray powder diffractogram of Celecoxib form Am FIG. 2 is Differential scanning calorimetry of Celecoxib form Am
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of crystalline Form Am of Celecoxib which comprises recovering Celecoxib from a solution in solvents under suitable conditions which yield a new crystalline Celecoxib Form Am.
Accordingly, the present invention is directed to new crystalline form Am, which is characterized by the following X-ray powder diffraction pattern expressed in terms of 29, d-spacings, and relative intensities with a relative intensity of >5% measured on a Philips Expert MPD (Holland) diffractometer with CuKα radiation, it should also be noted that the computer generated, unrounded numbers are listed in this table 1.
Table: 1 X-Ray Diffraction data of Celecoxib form Am

Sr. No. 29 value d-spacing Significance Relative
intensity [%]
1 5.5567 15.90458 2.6984 6.43
2 10.9487 8.08106 1.0972 5.15
3 13.145 6.73539 1.4071 1.79
4 14.9105 5.94164 2.7311 9.56
5 16.3307 5.42797 7.588 70.29
6 19.6769 4.51181 1.1003 3.02
7 21.9086 4.05701 16.8163 100

Table 1 Continued.
Sr. No. 28 value d-spacing Significance Relative
intensity [%]
8 22.3318 3.98107 4.1607 27.87
9 27.4262 3.25208 4.3101 24.63
10 29.9103 2.9874 2.5078 26.48
11 32.9179 2.72101 1.2745 12.3
12 35.2692 2.54481 1.1491 13.87
13 38.4155 2.34331 1.7885 17.07
The present invention describes the process for the preparation of Celecoxib novel crystalline form Am as designated by us. Reaction Scheme 1:

The present application provides an improved process for the preparation of celecoxib of Formula (1) via a reaction of 4,4,4-trifluoro-l-[4-(methyl)phenyl]-butane-1,3-dione of formula (2) with 4-sulphonamido phenylhydrazine hydrochloride of Formula (3) in water.
The compound of Formula (2) and Formula (3) may prepared by any method, including those that may be known in the art. For example 4.4,4-trifluoro-l-[4-(methy])pheny]]-butane-l,3-dione of Formula (2) may be prepared by the reaction of 4-methylacetophenone with ethyl trifluoro acetate in the presence of base and an organic

solvent. Suitable base is sodium methoxide and suitable organic solvent is methanol. The reaction may be carried out at temperature ranging from about 25°C to about reflux temperature of the solvent.
Present invention also provides a process for purification of Celecoxib, which comprises;
(i) Providing a solution of Celecoxib in a mixture of an aliphatic ketone and an aromatic hydrocarbon solvent;
(ii) Causing crystallization in the solution to obtain a solid precipitate; and (iii) Isolating the solid precipitate as substantially purified Celecoxib. The aromatic hydrocarbon solvent include, but not limited to at least one of toluene, benzene, xylene, ethyl benzene or mixture thereof, preferably the aromatic hydrocarbon solvent used is toluene. The aliphatic ketone solvent used for providing solution of Celecoxib is acetone.
The dissolution of Celecoxib in a solvent mixture may be performed at an elevated temperature, if required to achieve desired concentration. Further, an activated charcoal treatment may be performed to remove the color impurities or to reduce the content of heavy metals, if any, or to remove the extraneous matter from the solution containing Celecoxib.
The crystallization from the resultant reaction mixture may be carried out by cooling the reaction mixture to a lower temperature of 25°-30°C.
The product may be isolated from the reaction mixture by filtration by suction. The obtained wet cake is further dried by air oven .The drying is carried out at temperature of about 70° C.
The Celecoxib of Formula (1) obtained by the process described herein is believed to be substantially free from impurities that are originated from process and/or degradation. Typically, Celecoxib obtained as described herein may have purity of at least about 99.5%, preferably at least about 99.8% by weight as determined by high-performance liquid chromatography (HPLC). In particular, Celecoxib obtained as described herein, in the state of powder (active pharmaceutical ingredient).

The crystallization conditions are well established to give crystalline form Am. The powder X-Ray diffraction pattern of the Celecoxib is given in Fig. 1 and 29 values are given in table 1.
The X-Ray diffraction pattern has also been compared with available crystalline forms disclosed in prior art, US 7,476,744 Page no. 28, Table 1 discloses different polymorphic forms, comparison is given below in table 2;
Table 2; Comparison of new crystalline form Am of Celecoxib with available prior art.

Form Melting point (°C) ∆H (j/g) IR Raman PXRD (2θ)
I 162.8 72 3356 cm-1 NA 5.5°, 5.7°, 7.2° and 16.6°
II 161.5 <84 None 721 cm-1 10.3°,13.8°and
17.7°
III 160.8 94 - - -
Novel form 159-160 - - - 5.55°, 10.94°,
by Amoli 13.14°, 14.91°,
organics 16.33°, 19.67°,
(Form Am) 21.90°, 22.33°, 27.42°, 29.91°, 32.91°, 35.26° and 38.41°
The Celecoxib Crystalline form Am under specific conditions shows the melting point around 159°-160°C. The DSC of Celecoxib is given in fig.2. The novel crystalline form Am can be further confirmed by its melting point which is 159°-160°C, while melting point reported in THE MERK INDEX Forteenth edition, Monograph, Page No. 323, monograph no, 1956. is 157°-159°C.

DSC is used to characterize the polymorphic forms of Celecoxib, invention is further confirmed by comparison with available prior art in US 7,476,744. Table 3: DSC comparison of new crystalline form Am of Celecoxib with available prior art.

Polymorphic Form Melting point (°C) Endotherm maximum (°C)
Form I 162.8 163.3
Form II 161.5 162.0
Form III 160.8 161.5
Novel form by Amoli organics (Form Am) 159-160 163.5
The distinct advantage of the present invention over the prior art can be summarized as follow:
(1) The present process, which describes the manufacturing process of Celecoxib crystalline form Am, which is a non-steroidal anti-inflammatory drug (NSAID), has the advantage of scaling up to the industrial level of production.
(2) The process uses safe reagents in the process which makes it for industrial scale operations.
(3) The yields in the process are high which makes it a cost effective process.
(4) Residual solvents play a very important role in the impurity profile of APIs as per the ICH Guidelines ICH Q3C (R4). In this process by carrying out the final step of condensation in the aqueous medium followed by crystallization, the residual solvents limits are well taken care of.
(5) A novel crystalline form may overcome preformulation difficulties associated with previously available forms of Celecoxib.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further described by reference to the following examples disclosing in detail the process for preparation of Celecoxib of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES
EXAMPLE 1 In a 20 liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser, charge deionized water (7.5 Liter) 4,4,4-trifluoro-I-[4-(methyl)phenyl]-butane-l,3-dione(1.5 Kg; 6.52x103mmoles) and 4-sulphonamido phenylhydrazine hydrochloride(1.45 kg; 6.5x103 mmoles). a resultant mixture was heated at 80oC to 85oC and maintained for 5 hours. The reaction mixture was cooled to 25°C to 30°C.The separated solid was filtered and washed with water (3 liter) wet-cake was collected and further processed for purification as given below in example 2.
EXAMPLE 2: Purification of crude Celecoxib Celecoxib wet-cake obtained in the process described above was taken into 20 liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser, mixture of acetone (0.75 liter) and toluene (15 liter) was added and the reaction mixture was heated to 80°C to 85°C for 30 minutes. Water was removed, the organic layer was washed twice with water and aqueous layer was separated. Activated carbon (0.3 Kg) was added and the reaction mixture was further heated to 80°C to 85°C. The reaction mixture was filtered and cooled to 25°C-30 °C. The separated solid was filtered, washed with toluene and then wet cake (2-1 Kg) was further taken for crystallization. (HPLC purity-99.8% & molar yield; 50.9%)
EXAMPLE 3: Crystallization of Celecoxib Celecoxib as obtained in Example 1 was charged In 20 liter 3-necKed flask, equipped with stirrer, thermometer and reflux condenser, with toluene (12 liter) and Acetone (0.6 liter) under stirring condition, resultant mixture was gradually heated to 85° - 87°C for 3 hours and activated carbon treatment was given. Then reaction mixture was filtered through hyflow and washed with toluene (0.7 liter), filtrate was collected and cooled to 25°-30°C, maintained for 1 hour, filtered and then washed with toluene (2x750 ml) and suck dry to get the desired Polymorph of Celecoxib form A. (HPLC purity-99.8% & molar yield; 84.8%)

EXAMPLE 4 In a 20 liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser, charge deionized water (9 Liter) 4,4,4-trifluoro-l-[4-(methyl)phenyl]-butane-l,3-dione(1.6 Kg; 6.95x103mmo]es) and 4-sulphonamido phenylhydrazine hydrochIoride(1.7 Kg; 7.57x103mmoles), a resultant mature was heated at 90°C to 100°C and maintained for 5 hours. The reaction mixture was cooled to 25°C to 30°C.The separated solid was filtered and washed with water (3.2 liter) wet-cake was collected and further processed for purification as given below.
EXAMPLE 5: Purification of crude Celecoxib Celecoxib wet-cake obtained in the process described above was taken into 20 liter 3-necked flask, equipped with stirred thermometer and reflux condenser, mixture of acetone (0.54 liter) and toluene (l0.8 liter) was added and the reaction mixture was heated to 80°C to 85°C for 30 minutes. Activated carbon (0.3 Kg) was added and the reaction mixture was further heated to 80°C to 85°C. The reaction mixture was cooled to 25°C-30 °C. The separated solid was filtered, washed with toluene and then further taken for crystallization.
EXAMPLE 6- Crystallization of Celecoxib Celecoxib as obtained in Example 5 was charged in 20 liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser, with toluene (12 liter) and Acetone (0.6 liter) under stirring condition, resultant mixture was gradually heated to 55° - 60°C for 3 hours and activated carbon treatment was given. Then reaction mixture was filtered through hyflow and wash with toluene (2x750 ml), filtrate was collected and cooled to 25°-30°C maintained for 1 hour, filtered and then washed with toluene (2x750ml) and suck dry to get the desired Polymorph of Celecoxib. (HPLC purity-99.3% & molar yield: 47%)
It is also be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween.

Thus, we claim:
(1) The Novel crystalline form Am of Celecoxib of the formula (1) and process for preparation thereof.

(2) A novel crystalline form Am of Celecoxib as described in claim 1 having an X-ray powder diffraction containing the following 20 values measured using CuKα radiation: 5.55, 10.94, 13.14, 14.91, 16.33, 19.67, 21.90, 22.33, 27.42, 29.91, 32.91, 35.26 and 38.41.
(3) A novel crystalline form Am of Celecoxib as described in claim 1 having the DSC as given in Fig.2,
(4) Melting point of the said crystalline form Am is around 159°-160°C.
(5) The process as described in claim 1 comprises condensing 4,4,4-trifluoro-l-[4-(methyl)pbenyl]-butane-l,3-dione of the formula (2) with 4-sulphonamido phenyl hydrazine hydrochloride of the formula (3) in water.


(6) The process described in claim (1) wherein the reaction is carried out at a temperature about 20°C to 100°C, more preferably 80°C.
(7) A process for purification of Celecoxib form Am comprises:
a. Providing a solution of Celecoxib in mixture of aromatic hydrocarbon like
toluene and aliphatic ketone like acetone ;
b. Causing crystallization in said solution to obtain a solid precipitate; and
c. Isolating the solid precipitate, which is substantially purified Celecoxib.
(8) The process of claim (7) in which the crystallization is effected by cooling from
25°C - 30°C for 1 hour.